Membrane exosomes are spherical membrane microvesicles, generally less than 200 nm in diameter. The exosomes are composed of a lipid bilayer containing a cytosolic fraction. Particular membrane vesicles are more specifically produced by cells, from intracellular compartments through fusion with the cytoplasmic membrane of a cell, resulting in their release into the extracellular biological fluids of an organism or into the supernatant of cells in culture. These exosomes may be released in a number of ways. The classical secretory pathway processes mainly traditional membrane signals bearing receptors through the endoplasmic Reticulum (ER) membrane (Lee et al., (2004) Annu. Rev. Cell Dev. Biol. 20, 87-123).
Secretory proteins are packaged into transport vesicles, delivered to the Golgi apparatus, and eventually released into the extracellular space. Alternatively, nonclassical secretory pathways mediate translocation of cytosolic, nonsignal bearing molecules into the extracellular space (Lippincott-Schwartz et al., (1989) Cell 56, 801-813; and Misumi et al., (1986) J. Biol. Chem. 261, 11398-11403). Two of these involve intracellular vesicles of the endocytic membrane system, such as secretory lysosomes (Muesch et al., (1990) Trends Biochem. Sci. 15, 86-88) and exosomes (Johnstone et al., (1987) J. Biol. Chem. 262, 9412-9420), the latter ones being internal vesicles of late endosomes or multivesicular bodies (MVB). Lysosomal contents gain access to the exterior of cells when specialized endocytic structures such as secretory lysosomes of cytotoxic T lymphocytes, fuse with the plasma membrane. Lumenal contents of late endocytic structures are released into the extracellular space when MVBs fuse with the plasma membrane resulting in release of the internal multivesicular endosomes into the extracellular space (called exosomes) along with their cargo molecules. Other nonclassical pathways involve direct translocation of cytosolic factors across the plasma membrane using protein conducting channels or a process called membrane blebbing (Nickel, W. (2005) Traffic. 6, 607-614). Membrane blebbing is characterized by shedding of plasma membrane-derived microvesicles into the extracellular space.
Exosome release has been demonstrated from different cell types in varied physiological contexts. It has been demonstrated that tumor cells secrete exosomes, such as exosomes in a regulated manner, which can carry tumor antigens that can be presented to antigen presenting cells (Patent Application No. WO99/03499). In addition, FasL or TNF containing exosomes are known to cause a state of immune privilege/immune suppression which can promote tumor growth. Similarly, virus-infected cells, including those infected by HIV are known to release Nef-containing exosomes (Guy et al., (1990) Virology 176, 413-425; and Campbell et al., (2008) Ethn. Dis. 18, S2-S9), which serve to suppress the immune system allowing HIV to survive. Exosome secretion has been shown to utilize the same endosomal trafficking pathway involved in virion release from infected cells (Sanfridson et al., (1997) Proc. Natl. Acad. Sci. U.S.A 94, 873-878; and Esser et al., (2001) J Virol. 75, 6173-6182).
Tumors are known to release large numbers of exosomes, which can cause immune suppression through immune cell killing or dysregulation, thereby promoting a state of immunosuppression that allows for rapid tumor growth (Lindner K. et al., 2015, Salido-Guadarrama I. et al., 2014). Similarly, HIV infections result in high numbers of exosomes, which appears to contribute to a state of immune privilege/suppression which ultimately could lead to Acquired Immune Deficiency Syndrome (AIDS).
The exosome secretion pathway serves a dual function in both regulation of the cancer homeostasis, the immune system and virion release of infected cells. In view of the foregoing, there is a need in the art for compositions and effective methods of treatment for inhibiting exosome release.